PROJECT SUMMARY/ABSTRACT Diabetes mellitus (DM) is the leading cause of vision loss among working aged adults. Its prevalence is increasing and despite the strides in knowledge and treatments, our understanding of the pathways leading to vision loss in DM remains limited. Hyperglycemia and duration of DM contribute to but do not fully explain the predisposition to develop diabetic retinal diseases. Given the predisposition for diabetic retinal diseases to cluster in families, genetic risk factors are thought to be important but none has so far been definitively implicated. Furthermore, data from small studies suggest that there are more phenotypes of diabetic retinal disease than are currently recognized in clinical practice. Diabetic retinal disease has traditionally been considered primarily a vascular process: diabetic retinopathy (DR) and diabetic macular edema (DME) are the main clinical manifestations. With improved imaging modalities and image analysis algorithms, there has been increasing recognition of a new clinical manifestation of diabetic retinal disease, diabetic retinal neurodegeneration (DRN). This is visible as alterations in thickness of retinal nerve fiber (RNFL) and/or ganglion cell layer (GCL) on optical coherence tomography (OCT) images. To date, DRN is poorly understood, and its role in clinical management of patients with DM has not been established. However, if retinal neurodegeneration occurs and is progressive, it can lead to profound visual difficulties for patients with DM. DRN may account for previously unexplained poor visual outcomes among patients with diabetic retinal disease despite standard of care treatment. Dr. Channa is a retina specialist, with prior research experience in retinal imaging and clinical trials of novel treatments for DME. In this K23 career development award she proposes to use a nationally representative dataset, the UK Biobank cohort to: 1) improve our understanding of DRN by determining RNFL and GCL thickness, using OCT imaging, in participants with DM (who have no DR or DME) compared to those who do not have DM 2) determine genetic factors associated with DR, DME and DRN. Dr. Channa proposes a career development plan, which includes mentorship, coursework, publications and clinical time. This will situate her as an independent clinician-scientist with expertise in translational research employing bioinformatics and computational skills in genomics and retinal image analysis to elucidate pathways of vision loss among patients with DM, ultimately leading to development of novel therapies. Her research work and career development will take place in the academic and collaborative environment of the largest medical center in the world, where she has institutional support and mentorship to develop as an independent clinician-scientist.